Positron emission tomography, also called PET imaging or a PET scan, is a powerful technology for studying biological processes non-invasively at the molecular level. Positron emission tomography, is a diagnostic examination that involves the acquisition of physiologic images based on the detection of subatomic particles. These particles are emitted from a radioactive substance, also known as radiolabelled PET tracers (i.e., molecules labeled with positron-emitting atoms such as positron-emitting halogens) given to the patient. The subsequent views of the human body are used to evaluate function.
PET images show the chemical functioning of an organ or tissue, unlike X-ray, CT, or MRI which show only body structure. Thus, PET imaging allows a physician to examine the heart, brain, and other organs, and is particularly useful for the detection of cancer, coronary artery disease and brain disease. For example, PET imaging is unique in its ability to determine whether a patient's heart muscle will benefit from coronary artery bypass surgery. PET imaging can also provide information to pinpoint and evaluate diseases of the brain. For example, PET imaging can show the region of the brain that is causing a patient's seizures and is useful in evaluating degenerative brain diseases such as Alzheimer's, Huntington's, and Parkinson's. Within the first few hours of a stroke, PET imaging may be useful in determining treatment therapies. PET imaging can also be used to investigate lesions such as carcinomas, and can be employed for diagnosis and staging of diseases as well as judging the efficacy of anti-cancer drugs.
Over the last decade, much research has been directed to exploring the radiosynthesis and in vivo pharmacology of radiolabelled antiviral and antileukemic nucleoside derivatives for use as radiotracers in PET imaging, including agents such as [125I]-2′-fluoro-5-iodo-1-β-D-arabinofuranosylcytosine (FIAC) (Perlman, et al., Int. J. Nucl. Med. Biol., 11:215-218 (1984)); [125I, 131I, 123I]-2′-fluoro-5-iodo-1-β-D-arabinofuranosyluracils (FIAU) (Misra, et al., Appl. Radiation Isotopes, 37:901-905 (1986)); [11C]-N-methylacyclovir (Wilson, et al., J. Lab. Compd. Radiopharm., 29:765-768 (1991)); and a [18F] derivative of 9-[(1,3-dihydroxy-2-propoxy)methyl] guanine (DHPG) (Alauddin, et al., 206th Meeting of the American Chemical Society, Chicago, Ill., Aug. 22-26 (1993); Alauddin, et al., Nucl Med Biol., 23:787-792 (1996); Alauddin, et al., Nucl Med Bio.,l 26:371-376 (1999)).
Imaging of organs, tissues or cellular proliferation in vivo using radiolabeled analogs of nucleosides such as [133I]-UdR and [11C]-thymidine, however, is plagued by extensive catabolism of the parent compounds following intravenous administration, limiting uptake into the DNA of tumor tissues. Such catabolic events include dehalogenation, cleavage of the sugar moieties from the base, and ring opening of the base. For example, administration of [125I] labeled FIAC results in extensive deiodination in vivo (Perlman, et al., 1984, supra). In addition, FIAU can be formed in vivo from deamination of administered FIAC (Chou, et al., Cancer Res., 41:3336-3342 (1981); Grant, et al., Biochem. Pharm., 31:1103-1108 (1982)). A similar situation to IUdR also exists during the metabolism of FIAU. Although FIAU is less likely than IUdR to be catabolized by enzymatic cleavage of the glycosyl-base bond, and can itself be incorporated into DNA, deiodination followed by methylation at the 5 position of the base also can occur prior to DNA incorporation (Chou, et al., (1981), supra; Grant, et al., (1982), supra).
Many fluorinated analogues of adenosine nucleoside have been synthesized and studied as potential antitumor and antiviral agents (Wright, et al., Carbohydrate Res., 6:347-354 (1968); Wright, et al., J. Org. Chem., 34:2932-2636 (1969); Ikehara, et al., Tetrahedron 34:1133-1138 (1978); Pankiewicz, et al., J. Org Chem., 57:553-559 (1992); Montgomery, et al., J. Med. Chem., 35:397-401 (1992); Carson, et al., Proc. Natl. Acad. Sci. USA, 89:2970-2974 (1992); Takahashi, et al., Cancer Chemother. Pharmacol 43:233-240 (1999); Kim, et al., J. Pharm. Chem., 85:339-344 (1996); Mikhailopulo, et al., J. Med Chem., 34: 2195-2202 (1991); Van Aerschot, et al., Antiviral Res., 12:133-150 (1989); Smee, et al., Antiviral Res., 18:151-1162 (1992)). Among these, 2′-deoxy-2′-fluoro-2-chloro-9-β-D-arabinofuranosyladenine has been found to be active against human colon tumor xenografts (Carson, supra; Takahashi, supra). The 2′-deoxy-2′-fluoroarabino compounds gained much attention as anticancer agents (Carson, supra; Takahashi, supra; Kim, supra), while the 3′-deoxy-3′-fluororibo compounds have shown antiviral activity (Mikhailopulo, et al., J. Med. Chem. 34:2195-2202 (1991); Van Aerschot, et al., Antiviral Res., 12:133-150 (1989); Smee, et al., Antiviral Res., 18:1151-1162 (1992)). However, little information is available regarding the biological properties of the xylo-derivative 3′-fluoro-9-β-D-xylofuranosyladenine (Wright, et al., Carbohydrate Res., 1968; 6:347-354; Robins, et al., J. Org. Chem., 39:1564-1570 (1974); Lewandowska, et al., Tetrahedron; 53:6295-6302 (1997)). [11C]-adenosine monophosphate has been synthesized in order to investigate its potential use for imaging of cancer (Mathews, et al. J. Nucl. Med., 43:362P (2002), and [14C]-adenosine has been shown to be a marker for myocardial blood flow in dogs.
The synthesis of unlabeled 2′-deoxy-2′-fluoro-9-β-D-arabinofuranosyladenine involves the incorporation of fluorine in the arabino configuration at C-2 of the sugar, followed by coupling with the purine base (Wright, et al., Carbohydrate Res. 1968; 6:347-354; Chu et al., Chem. Pharm. Bull., 37:336-339 (1989)). Another reported synthesis involves treatment of N6-3′, 5′-tritrityladenosine with (diethylamino)-sulfur trifluoride (DAST) (Pankiewicz, et al., J. Org. Chem., 57:553-559 (1992); Lewandowska, et al., Tetrahedron, 53:6295-6302 (1997)). However, DAST is not a suitable reagent for radiochemical synthesis of the [18F]-labeled analog of this compound due to the unavailability of the 18F-labeled reagent and the required long reaction time.
There is thus a long-felt need in the art for a suitable partially or non-catabolized imaging agent (e.g., nucleoside analog) for use in, e.g., tumor proliferation studies with PET. Except for limited catabolism, an ideal tracer should share the other in vivo characteristics of the nucleoside, including cell transport, phosphorylation by mammalian kinase, and incorporation into DNA. In particular, development of a partially or non-catabolized purine analog would greatly simplify imaging and modeling approaches and potentially provide higher target to background ratios due to more selective incorporation of radiotracer.